Cancer Causes Control DOI 10.1007/s10552-014-0473-4
ORIGINAL PAPER
Conization as a marker of persistent cervical human papillomavirus (HPV) infection and risk of gastrointestinal cancer: a Danish 34-year nationwide cohort study Jakob Kirkega˚rd • Dora Ko¨rmendine´ Farkas • Mette Søgaard • Sigru´n Alba Jo´hannesdo´ttir Schmidt Eva Bjerre Ostenfeld • Deirdre Cronin-Fenton
•
Received: 9 July 2014 / Accepted: 6 October 2014 Ó Springer International Publishing Switzerland 2014
Abstract Purpose Persistent cervical infection with human papillomavirus (HPV) may be a marker of poor immune function and thus associated with an increased cancer risk. HPV infection is implicated in all cases of cervical cancer, but except for anal and esophageal cancers, the association between persistent HPV infection and gastrointestinal cancer has not been investigated. Methods We performed a nationwide population-based cohort study of 83,008 women undergoing cervical conization between 1978 and 2011, using cervical conization as a marker of chronic HPV infection. We computed standardized incidence ratios (SIRs) as a measure of the relative risk of each cancer comparing women undergoing conization with that expected in the general population. We also calculated absolute risks. Results During follow-up, 988 GI cancers occurred versus 880 expected among 83,008 women followed for a median of 14.9 years, corresponding to a SIR of 1.1 (95 % CI 1.1–1.2). Risks were increased for anal (SIR 2.9; 95 % CI 2.3–3.5) and esophageal (SIR 1.5; 95 % CI 1.1–2.0) cancers, with suggested increased risks of cancers of the gallbladder and biliary tract (SIR 1.3; 95 % CI 0.90–1.8), pancreas (SIR 1.2; 95 % CI 0.97–1.4), and liver (SIR 1.1; 95 % CI 0.79–1.6).
Electronic supplementary material The online version of this article (doi:10.1007/s10552-014-0473-4) contains supplementary material, which is available to authorized users. J. Kirkega˚rd D. K. Farkas M. Søgaard S. A. J. Schmidt E. B. Ostenfeld D. Cronin-Fenton (&) Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle´ 43-45, 8200 Aarhus N, Denmark e-mail: [email protected] J. Kirkega˚rd Department of Surgical Gastroenterology L, Aarhus University Hospital, L-forskning, bygning 1C, Nørrebrogade 44, 8000 Aarhus N, Denmark
The SIRs decreased with increasing follow-up time. The risks of gastric, small intestinal, colon, or rectal cancers were not elevated. Overall, the absolute cancer risk was 0.18 % (95 % CI 0.15–0.21) after 5 years. Conclusions The relative risks of several gastrointestinal cancers were raised among women who underwent cervical conization for persistent HPV infection, but the absolute risks were low. Keywords Anal cancer Conization Esophageal cancer Hepatobiliary cancer Human papillomavirus Pancreatic cancer Introduction Human papilloma virus (HPV) is prevalent in the uterine cervix of approximately 10 % of all women worldwide and is implicated in all cases of cervical cancer [1, 2]. For most women, HPV infection is transient and resolves spontaneously [3], but others develop a persistent infection, increasing their risk of invasive cervical cancer [1]. The physiology of viral clearance is not completely understood, but factors such as host genetic susceptibility, immune function, and behavioral factors are likely to play a role [4, 5]. Inflammatory cells are an essential part of cancer biology, and chronic inflammation is known to enhance malignant transformation via changes in growth factor signaling in many organs [6]. For example, patients affected by chronic pancreatitis have an increased incidence of pancreatic cancer [7], while those with inflammatory bowel disease have an increased risk of colorectal cancer [8]. Thus, patients with systemic chronic inflammation due to persistent HPV infection may have an increased risk of cancer in the gastrointestinal tract.
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The association between persistent HPV infection and various gastrointestinal cancers is interesting. An association with colorectal cancer has been suggested [9], whereas HPV does not seem to have a role in the development of gastric cancer [10, 11]. Further, HPV is known to cause anal cancer [12], and although the association between HPV infection and esophageal cancer has been extensively investigated, results are inconclusive [13]. Cervical conization is a minor surgical procedure used to remove cervical tissue with HPV-associated dysplasia and is therefore a definitive marker of HPV infection. We conducted a nationwide Danish cohort study to explore the hypothesis that persistent HPV infection, as measured by conization, increases the susceptibility to cancer in the gastrointestinal tract.
Materials and methods
Table 1 Characteristics for 83,008 women undergoing conization for cervical dysplasia in Denmark, 1978–2011 Characteristic
n
%
Total study population
83,008
100.0
18–29 years
27,028
32.6
30–49 years
48,049
57.9
50–69 years
7,263
8.7
668
0.8
Year of conization 1978–1982
11,733
14.1
1983–1987
10,827
13.0
1988–1992
11,998
14.5
1993–1997
12,699
15.3
1998–2002
13,552
16.3
2003–2007
12,382
14.9
2008–2011
9,817
11.9
77,257
93.1
5,265
6.3
486
0.6
Age at conization
C 70 years
Charlson comorbidity index score Low (0)
We conducted a nationwide population-based Danish cohort study during the period 1 January 1978 to 31 December 2011. Using the civil registration number, a unique identification number assigned to all Danish residents at birth or immigration, individual-level data linkage of several Danish medical registries was possible [14]. Study population We used the Danish National Patient Registry (DNPR) to identify all women aged 18 or above, who underwent cervical conization at a public hospital in Denmark during the study period. The DNPR has registered all inpatient hospital admissions since 1977 and all outpatient clinic and emergency department visits since 1995 [15]. In the DNPR, surgical procedures are classified according to the Danish Classification of Surgical Procedures and Therapy, and all diagnoses are classified according to the 8th revision of the International Classification of Diseases (ICD-8) until 1994 and the 10th revision (ICD-10) thereafter (Supplemental Table 1). To limit heterogeneity of the study population, all women born outside Denmark were excluded. Data on cancers and comorbid conditions Using the Danish Cancer Registry, which contains data on almost all cancer diagnoses in Denmark since 1943 [16], we retrieved data on the diagnoses of the following cancers for each woman included in the study: esophageal (squamous cell carcinoma and adenocarcinoma), gastric, small intestinal, colon, rectal, anal, liver, gallbladder and biliary tract, and pancreatic cancers. We excluded all patients with
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Moderate (1–2) Severe (C 3)
any of these gastrointestinal cancers before the date of conization. We assessed comorbid conditions recorded in the DNPR using the Charlson Comorbidity Index (CCI) score [17]. This score is based on disease categories, each weighted according to its impact on 1-year mortality and can be used to assess the overall burden of comorbidity [18]. We defined three levels of comorbidity: no (score 0), moderate (score 1–2), and severe comorbidity (score C 3) and excluded gastrointestinal cancer from the CCI score. Statistical analyses We followed women from the date of conization until the date of the first gastrointestinal cancer diagnosis, death, emigration, or 31 December 2011, whichever occurred first. We calculated standardized incidence ratios (SIRs) as a measure of the relative risk, comparing observed number of cancers among women who had a conization with the expected number. Expected numbers of cancers were estimated based on national cancer incidence rates by age (1-year age groups), sex, and calendar year (1-year intervals) multiplied by the time of follow-up observed in our cohort. We computed corresponding 95 % confidence intervals (CIs) for the SIRs under the assumption that the observed number of cases in a specific category followed a Poisson distribution. Exact 95 % CIs were used when the observed number was less than 10; otherwise, Byar’s approximation was used [19]. We performed analyses for each type of cancer stratified by duration of follow-up (\1,
Cancer Causes Control Table 2 SIRs for gastrointestinal cancers in 83,008 women undergoing conization for cervical dysplasia in Denmark, 1978–2011, stratified by time of follow-up Site of cancer
Overall n
Overall Esophagusa Squamous carcinoma Adenocarcinoma Gastric Small intestines
SIR
\1 year
1–5 years
[5 years
n
SIR
n
SIR
n
SIR
988
1.1 (1.1–1.2)
32
1.7 (1.2–2.4)
106
1.2 (1.0–1.5)
850
1.1 (1.0–1.2)
55
1.5 (1.1–2.0)
1
1.6 (0.04–9.0)
8
2.7 (1.2–5.3)
46
1.4 (1.0–1.9)
30 8
1.4 (0.91–1.9) 1.1 (0.48–2.2)
1 0
2.6 (0.06–14.2) 0.00 (–)
3 0
1.6 (0.33–4.6) 0.00 (–)
26 8
1.3 (0.85–1.9) 1.2 (0.53–2.4)
64
1.0 (0.79–1.3)
2
1.1 (0.13–4.0)
3
0.38 (0.08–1.1)
59
1.1 (0.86–1.5)
0.00 (–)
0
0.00 (–)
13
0.92 (0.49–1.6)
0
Colon
366
0.97 (0.88–1.1)
14
Rectum
1.8 (0.96–3.0)
48
13
1.1 (0.56–1.8)
1.3 (0.98–1.8)
304
0.91 (0.81–1.0)
180
1.0 (0.88–1.2)
6
1.6 (0.59–3.5)
18
1.1 (0.63–1.7)
156
1.0 (0.86–1.2)
Anal canal
97
2.9 (2.3–3.5)
5
7.1 (2.3–16.6)
6
1.8 (0.66–3.9)
86
2.9 (2.3–3.6)
Liver
33
1.1 (0.79–1.6)
1
1.4 (0.03–7.5)
3
0.92 (0.19–2.7)
29
1.2 (0.78–1.7)
Gallbladder and biliary tract
37
1.3 (0.90–1.8)
2
3.0 (0.36–10.7)
3
1.0 (0.21–2.9)
32
1.3 (0.87–1.8)
143
1.2 (0.97–1.4)
1
0.42 (0.01–2.3)
17
1.5 (0.89–2.5)
125
1.1 (0.94–1.3)
Pancreas
Numbers in parentheses indicates 95 % CIs a
Squamous carcinoma and adenocarcinoma combined is less than the total number of esophageal cancers observed, which is due to another morphology code used for the remaining cases
1–5,[5 years, and overall). We also computed the absolute risk of cancer, considering death as a competing risk. Ethical considerations This study was approved by the Danish Data Protection Agency (record number 1-16-02-1-08).
Table 2). In site-specific analyses, the SIR varied from 0.92 to 2.9 with highest risks for cancers of the anus (SIR 2.9; 2.3–3.5), esophagus (SIR 1.5; 95 % CI 1.1–2.0), and gallbladder and biliary tract (SIR 1.3; 95 % CI 0.90–1.8), and a suggested increase in the risk of pancreatic (SIR 1.2; 95 % CI 0.97–1.4) and liver (SIR 1.1; 95 % CI 0.79–1.6) cancer. No increase in cancer risk was found for gastric, small intestinal, colon, or rectal cancer (Table 2).
Results
Cancer risk according to the duration of follow-up
We identified 87,362 adult women, who underwent cervical conization between 1978 and 2011. Of these, 4,354 women were excluded because of birthplace outside Denmark. Thus, we included 83,008 women (Table 1) followed for a total of 1,298,222 person-years with a median of 14.9 years (interquartile range (IQR) 7.7–23.2 years). Median age at time of conization was 33.8 years (IQR 28.4–41.1 years). The majority of the patients (93.1 %) had no recorded comorbidities, 6.3 % had moderate comorbidity score, and 0.6 % had severe comorbidity score.
The SIR for all gastrointestinal cancers in total decreased from 1.7 (95 % CI 1.2–2.4) to 1.1 (95 % CI 1.0–1.2) with increasing length of follow-up time (Table 2). The risks of anal (SIR 7.1; 95 % CI 2.3–16.6), gallbladder and biliary tract (SIR 3.0; 95 % CI 0.36–10.7), and colon (SIR 1.8; 95 % CI 0.96–3.0) cancers were strongly elevated within the first year after conization but decreased with increasing follow-up time. Nonetheless, the risk of anal, esophageal, gallbladder and biliary tract, pancreatic, and liver cancers remained elevated after 5 years of follow-up.
Overall cancer risk Discussion In total, 988 gastrointestinal cancers were observed compared to 880 expected cancers, corresponding to a SIR of 1.1 (95 % CI 1.1–1.2). The absolute risk of developing a gastrointestinal cancer was 0.18 % (95 % CI 0.15–0.21) at 5 years and 3.4 % (95 % CI 3.1–3.7) for the entire followup period. Absolute risks for site-specific cancers were in general low, even at the end of follow-up (Supplemental
In this large registry-based study of 83,008 Danish women undergoing cervical conization—a marker of persistent HPV infection—we observed an increased risk of anal and esophageal cancers compared with the general population. Increased, although lower, effect estimates were observed for cancers of the gallbladder and biliary tract, pancreas,
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and liver. Overall cancer risk decreased with increasing length of follow-up time but remained elevated among women who had undergone conization compared with the general population even after more than 5 years of followup. To the best of our knowledge, the potentially increased risk of gallbladder and biliary tract, pancreatic, and liver cancers in this study is a novel finding. The increased risk of esophageal cancer correlates with findings from some papers [20–24], which examined the presence of HPV DNA in esophageal tumor samples, whereas other studies [25–29] failed to identify an association. Our findings may be attributable to several factors. Persistent HPV infection, due to compromised viral clearance, contributes to a persistent activation of the immune system, which in turn can promote tumorigenesis through chronic inflammation [6]. Furthermore, confounding due to unmeasured risk factors such as tobacco smoking could also have impacted our findings, as tobacco smoking is associated with poor clearance of HPV infection [30]. Tobacco smoking sometimes correlates with other lifestyle factors such as increased alcohol consumption, and both of these also increase the risk of several gastrointestinal cancers [31– 34], which may explain, at least in part, the observed increased risk of esophageal, gallbladder and biliary tract, pancreatic, and liver cancers. In addition, esophageal squamous carcinoma is said to be more closely related to smoking compared with adenocarcinoma [35]. As the risk increase for esophageal squamous cell carcinoma was more pronounced than that for esophageal adenocarcinoma, tobacco smoking may have also contributed to the increased risk of esophageal cancer among women with persistent HPV infection. Although smoking may have confounded our findings with regard to cancers strongly related to smoking, such as esophageal squamous cell carcinoma, we observed no association between conization and gastric and colon cancers, which are possibly also related to smoking [36, 37]. Therefore, tobacco smoking is unlikely to entirely explain our findings. We stratified our analyses by the duration of follow-up to examine the temporality of the association between persistent HPV infection and gastrointestinal cancers. This analysis revealed a decrease in overall relative cancer risk with increasing length of follow-up, but the SIRs remained elevated after more than 5 years of follow-up for esophageal, anal, liver, gallbladder and biliary tract, and pancreatic cancers. This finding could indicate an actual association between persistent HPV infection and these cancers, but it could also be attributable to residual confounding from, for example, poor health awareness and lifestyle factors, for which we had no information. Although we also found strongly elevated risks of anal, gallbladder and biliary tract cancers, and colon cancer in
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the first year of follow-up, our estimates had low precision. The increased 1-year risk may result from increased medical surveillance among women undergoing conization for cervical dysplasia (i.e., surveillance bias). In addition, cancers occurring less than 1 year after conization are unlikely to be caused by persistent HPV infection. A major strength of this study is the population-based design in the setting of a uniform tax-financed health care system with equal access for all residents allowing long-term and complete follow-up. The prospective data collection via use of valid electronic registries minimizes the possibilities of underreporting of cancer diagnoses. The increased risk of anal cancer observed in our study is consistent with findings from previous studies, which report a positive association between persistent HPV infection and anal cancer [12], strengthening the validity of our findings. Limitations include a lack of data on potential confounders such as environmental or lifestyle exposures including, among others, tobacco smoking, genetic susceptibility, sexual behavior, and alcohol consumption. We also lacked information on conizations performed at outpatient departments before 1995. Incomplete registration of conization before 1995 would most likely lead to non-differential misclassification and thus an underestimation of a true association. On the other hand, when comparing patients undergoing conization after 1995, we found a lower overall cancer risk among women treated in an outpatient department (data not shown). If such a difference was also present before 1995, we have overestimated the association early in the follow-up period (i.e., before 1995). Moreover, procedures performed at private clinics are not registered in the DNPR and are therefore not included in this study. The proportion of patients treated at private clinics is unknown but probably small due to the tax-financed health care system in Denmark. HPV-infected patients treated by methods other than cervical conization are not included in this study. However, cervical conization is the standard therapy for persistent cervical HPV infection in Denmark, and we, therefore, expect our cohort to comprise the majority of all women treated for persistent HPV infection in the study period. If women with persistent HPV infection are not included in this study, our findings may have been underestimated. In theory, we might have included patients with manifest cervical cancer, which are known to have a higher risk of HPV- and radiation-related secondary cancers [38]. This possible selection problem could lead to an overestimation of gastrointestinal cancer risk. However, only women with very early stages of cervical cancer are treated with conization, and these patients do not require adjuvant radiation therapy. Thus, the observed increase in gastrointestinal cancer risk is unlikely to be explained by a previous history of cervical cancer.
Cancer Causes Control
Whereas chronic HPV infection is known to play a key role in the development of cancers of the anus, uterine cervix, and head and neck [39], the evidence of a role of HPV in the development of esophageal squamous cell carcinoma is inconclusive [13]. This study is the first large registry-based study to investigate the association between chronic HPV infection and other gastrointestinal cancers, which usually have poor survival rates. Our findings imply an increased risk of some gastrointestinal cancers among women with a history of HPV infection, as estimated via cervical conization. Although the absolute risks were low, primary HPV prevention via vaccination may have extended benefit to the control of other cancers. In this hypothesis-generating study, we demonstrated an increased incidence of anal and esophageal cancers, and possible increases in the incidence of gallbladder and biliary tract, pancreatic, and liver cancers more than 5 years after conization. Our findings imply an association between chronic cervical HPV infection and subsequent carcinogenesis in other organs. Acknowledgments The study was supported by a grant from the Danish Cancer Society (R73-A4284-13-S17) and from Aarhus University Research Foundation.
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13.
14.
15.
16. Conflict of interest of interests.
The authors declare that they have no conflict 17.
18.
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ORIGINAL PAPER
Conization as a marker of persistent cervical human papillomavirus (HPV) infection and risk of gastrointestinal cancer: a Danish 34-year nationwide cohort study Jakob Kirkega˚rd • Dora Ko¨rmendine´ Farkas • Mette Søgaard • Sigru´n Alba Jo´hannesdo´ttir Schmidt Eva Bjerre Ostenfeld • Deirdre Cronin-Fenton
•
Received: 9 July 2014 / Accepted: 6 October 2014 Ó Springer International Publishing Switzerland 2014
Abstract Purpose Persistent cervical infection with human papillomavirus (HPV) may be a marker of poor immune function and thus associated with an increased cancer risk. HPV infection is implicated in all cases of cervical cancer, but except for anal and esophageal cancers, the association between persistent HPV infection and gastrointestinal cancer has not been investigated. Methods We performed a nationwide population-based cohort study of 83,008 women undergoing cervical conization between 1978 and 2011, using cervical conization as a marker of chronic HPV infection. We computed standardized incidence ratios (SIRs) as a measure of the relative risk of each cancer comparing women undergoing conization with that expected in the general population. We also calculated absolute risks. Results During follow-up, 988 GI cancers occurred versus 880 expected among 83,008 women followed for a median of 14.9 years, corresponding to a SIR of 1.1 (95 % CI 1.1–1.2). Risks were increased for anal (SIR 2.9; 95 % CI 2.3–3.5) and esophageal (SIR 1.5; 95 % CI 1.1–2.0) cancers, with suggested increased risks of cancers of the gallbladder and biliary tract (SIR 1.3; 95 % CI 0.90–1.8), pancreas (SIR 1.2; 95 % CI 0.97–1.4), and liver (SIR 1.1; 95 % CI 0.79–1.6).
Electronic supplementary material The online version of this article (doi:10.1007/s10552-014-0473-4) contains supplementary material, which is available to authorized users. J. Kirkega˚rd D. K. Farkas M. Søgaard S. A. J. Schmidt E. B. Ostenfeld D. Cronin-Fenton (&) Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle´ 43-45, 8200 Aarhus N, Denmark e-mail: [email protected] J. Kirkega˚rd Department of Surgical Gastroenterology L, Aarhus University Hospital, L-forskning, bygning 1C, Nørrebrogade 44, 8000 Aarhus N, Denmark
The SIRs decreased with increasing follow-up time. The risks of gastric, small intestinal, colon, or rectal cancers were not elevated. Overall, the absolute cancer risk was 0.18 % (95 % CI 0.15–0.21) after 5 years. Conclusions The relative risks of several gastrointestinal cancers were raised among women who underwent cervical conization for persistent HPV infection, but the absolute risks were low. Keywords Anal cancer Conization Esophageal cancer Hepatobiliary cancer Human papillomavirus Pancreatic cancer Introduction Human papilloma virus (HPV) is prevalent in the uterine cervix of approximately 10 % of all women worldwide and is implicated in all cases of cervical cancer [1, 2]. For most women, HPV infection is transient and resolves spontaneously [3], but others develop a persistent infection, increasing their risk of invasive cervical cancer [1]. The physiology of viral clearance is not completely understood, but factors such as host genetic susceptibility, immune function, and behavioral factors are likely to play a role [4, 5]. Inflammatory cells are an essential part of cancer biology, and chronic inflammation is known to enhance malignant transformation via changes in growth factor signaling in many organs [6]. For example, patients affected by chronic pancreatitis have an increased incidence of pancreatic cancer [7], while those with inflammatory bowel disease have an increased risk of colorectal cancer [8]. Thus, patients with systemic chronic inflammation due to persistent HPV infection may have an increased risk of cancer in the gastrointestinal tract.
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The association between persistent HPV infection and various gastrointestinal cancers is interesting. An association with colorectal cancer has been suggested [9], whereas HPV does not seem to have a role in the development of gastric cancer [10, 11]. Further, HPV is known to cause anal cancer [12], and although the association between HPV infection and esophageal cancer has been extensively investigated, results are inconclusive [13]. Cervical conization is a minor surgical procedure used to remove cervical tissue with HPV-associated dysplasia and is therefore a definitive marker of HPV infection. We conducted a nationwide Danish cohort study to explore the hypothesis that persistent HPV infection, as measured by conization, increases the susceptibility to cancer in the gastrointestinal tract.
Materials and methods
Table 1 Characteristics for 83,008 women undergoing conization for cervical dysplasia in Denmark, 1978–2011 Characteristic
n
%
Total study population
83,008
100.0
18–29 years
27,028
32.6
30–49 years
48,049
57.9
50–69 years
7,263
8.7
668
0.8
Year of conization 1978–1982
11,733
14.1
1983–1987
10,827
13.0
1988–1992
11,998
14.5
1993–1997
12,699
15.3
1998–2002
13,552
16.3
2003–2007
12,382
14.9
2008–2011
9,817
11.9
77,257
93.1
5,265
6.3
486
0.6
Age at conization
C 70 years
Charlson comorbidity index score Low (0)
We conducted a nationwide population-based Danish cohort study during the period 1 January 1978 to 31 December 2011. Using the civil registration number, a unique identification number assigned to all Danish residents at birth or immigration, individual-level data linkage of several Danish medical registries was possible [14]. Study population We used the Danish National Patient Registry (DNPR) to identify all women aged 18 or above, who underwent cervical conization at a public hospital in Denmark during the study period. The DNPR has registered all inpatient hospital admissions since 1977 and all outpatient clinic and emergency department visits since 1995 [15]. In the DNPR, surgical procedures are classified according to the Danish Classification of Surgical Procedures and Therapy, and all diagnoses are classified according to the 8th revision of the International Classification of Diseases (ICD-8) until 1994 and the 10th revision (ICD-10) thereafter (Supplemental Table 1). To limit heterogeneity of the study population, all women born outside Denmark were excluded. Data on cancers and comorbid conditions Using the Danish Cancer Registry, which contains data on almost all cancer diagnoses in Denmark since 1943 [16], we retrieved data on the diagnoses of the following cancers for each woman included in the study: esophageal (squamous cell carcinoma and adenocarcinoma), gastric, small intestinal, colon, rectal, anal, liver, gallbladder and biliary tract, and pancreatic cancers. We excluded all patients with
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Moderate (1–2) Severe (C 3)
any of these gastrointestinal cancers before the date of conization. We assessed comorbid conditions recorded in the DNPR using the Charlson Comorbidity Index (CCI) score [17]. This score is based on disease categories, each weighted according to its impact on 1-year mortality and can be used to assess the overall burden of comorbidity [18]. We defined three levels of comorbidity: no (score 0), moderate (score 1–2), and severe comorbidity (score C 3) and excluded gastrointestinal cancer from the CCI score. Statistical analyses We followed women from the date of conization until the date of the first gastrointestinal cancer diagnosis, death, emigration, or 31 December 2011, whichever occurred first. We calculated standardized incidence ratios (SIRs) as a measure of the relative risk, comparing observed number of cancers among women who had a conization with the expected number. Expected numbers of cancers were estimated based on national cancer incidence rates by age (1-year age groups), sex, and calendar year (1-year intervals) multiplied by the time of follow-up observed in our cohort. We computed corresponding 95 % confidence intervals (CIs) for the SIRs under the assumption that the observed number of cases in a specific category followed a Poisson distribution. Exact 95 % CIs were used when the observed number was less than 10; otherwise, Byar’s approximation was used [19]. We performed analyses for each type of cancer stratified by duration of follow-up (\1,
Cancer Causes Control Table 2 SIRs for gastrointestinal cancers in 83,008 women undergoing conization for cervical dysplasia in Denmark, 1978–2011, stratified by time of follow-up Site of cancer
Overall n
Overall Esophagusa Squamous carcinoma Adenocarcinoma Gastric Small intestines
SIR
\1 year
1–5 years
[5 years
n
SIR
n
SIR
n
SIR
988
1.1 (1.1–1.2)
32
1.7 (1.2–2.4)
106
1.2 (1.0–1.5)
850
1.1 (1.0–1.2)
55
1.5 (1.1–2.0)
1
1.6 (0.04–9.0)
8
2.7 (1.2–5.3)
46
1.4 (1.0–1.9)
30 8
1.4 (0.91–1.9) 1.1 (0.48–2.2)
1 0
2.6 (0.06–14.2) 0.00 (–)
3 0
1.6 (0.33–4.6) 0.00 (–)
26 8
1.3 (0.85–1.9) 1.2 (0.53–2.4)
64
1.0 (0.79–1.3)
2
1.1 (0.13–4.0)
3
0.38 (0.08–1.1)
59
1.1 (0.86–1.5)
0.00 (–)
0
0.00 (–)
13
0.92 (0.49–1.6)
0
Colon
366
0.97 (0.88–1.1)
14
Rectum
1.8 (0.96–3.0)
48
13
1.1 (0.56–1.8)
1.3 (0.98–1.8)
304
0.91 (0.81–1.0)
180
1.0 (0.88–1.2)
6
1.6 (0.59–3.5)
18
1.1 (0.63–1.7)
156
1.0 (0.86–1.2)
Anal canal
97
2.9 (2.3–3.5)
5
7.1 (2.3–16.6)
6
1.8 (0.66–3.9)
86
2.9 (2.3–3.6)
Liver
33
1.1 (0.79–1.6)
1
1.4 (0.03–7.5)
3
0.92 (0.19–2.7)
29
1.2 (0.78–1.7)
Gallbladder and biliary tract
37
1.3 (0.90–1.8)
2
3.0 (0.36–10.7)
3
1.0 (0.21–2.9)
32
1.3 (0.87–1.8)
143
1.2 (0.97–1.4)
1
0.42 (0.01–2.3)
17
1.5 (0.89–2.5)
125
1.1 (0.94–1.3)
Pancreas
Numbers in parentheses indicates 95 % CIs a
Squamous carcinoma and adenocarcinoma combined is less than the total number of esophageal cancers observed, which is due to another morphology code used for the remaining cases
1–5,[5 years, and overall). We also computed the absolute risk of cancer, considering death as a competing risk. Ethical considerations This study was approved by the Danish Data Protection Agency (record number 1-16-02-1-08).
Table 2). In site-specific analyses, the SIR varied from 0.92 to 2.9 with highest risks for cancers of the anus (SIR 2.9; 2.3–3.5), esophagus (SIR 1.5; 95 % CI 1.1–2.0), and gallbladder and biliary tract (SIR 1.3; 95 % CI 0.90–1.8), and a suggested increase in the risk of pancreatic (SIR 1.2; 95 % CI 0.97–1.4) and liver (SIR 1.1; 95 % CI 0.79–1.6) cancer. No increase in cancer risk was found for gastric, small intestinal, colon, or rectal cancer (Table 2).
Results
Cancer risk according to the duration of follow-up
We identified 87,362 adult women, who underwent cervical conization between 1978 and 2011. Of these, 4,354 women were excluded because of birthplace outside Denmark. Thus, we included 83,008 women (Table 1) followed for a total of 1,298,222 person-years with a median of 14.9 years (interquartile range (IQR) 7.7–23.2 years). Median age at time of conization was 33.8 years (IQR 28.4–41.1 years). The majority of the patients (93.1 %) had no recorded comorbidities, 6.3 % had moderate comorbidity score, and 0.6 % had severe comorbidity score.
The SIR for all gastrointestinal cancers in total decreased from 1.7 (95 % CI 1.2–2.4) to 1.1 (95 % CI 1.0–1.2) with increasing length of follow-up time (Table 2). The risks of anal (SIR 7.1; 95 % CI 2.3–16.6), gallbladder and biliary tract (SIR 3.0; 95 % CI 0.36–10.7), and colon (SIR 1.8; 95 % CI 0.96–3.0) cancers were strongly elevated within the first year after conization but decreased with increasing follow-up time. Nonetheless, the risk of anal, esophageal, gallbladder and biliary tract, pancreatic, and liver cancers remained elevated after 5 years of follow-up.
Overall cancer risk Discussion In total, 988 gastrointestinal cancers were observed compared to 880 expected cancers, corresponding to a SIR of 1.1 (95 % CI 1.1–1.2). The absolute risk of developing a gastrointestinal cancer was 0.18 % (95 % CI 0.15–0.21) at 5 years and 3.4 % (95 % CI 3.1–3.7) for the entire followup period. Absolute risks for site-specific cancers were in general low, even at the end of follow-up (Supplemental
In this large registry-based study of 83,008 Danish women undergoing cervical conization—a marker of persistent HPV infection—we observed an increased risk of anal and esophageal cancers compared with the general population. Increased, although lower, effect estimates were observed for cancers of the gallbladder and biliary tract, pancreas,
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and liver. Overall cancer risk decreased with increasing length of follow-up time but remained elevated among women who had undergone conization compared with the general population even after more than 5 years of followup. To the best of our knowledge, the potentially increased risk of gallbladder and biliary tract, pancreatic, and liver cancers in this study is a novel finding. The increased risk of esophageal cancer correlates with findings from some papers [20–24], which examined the presence of HPV DNA in esophageal tumor samples, whereas other studies [25–29] failed to identify an association. Our findings may be attributable to several factors. Persistent HPV infection, due to compromised viral clearance, contributes to a persistent activation of the immune system, which in turn can promote tumorigenesis through chronic inflammation [6]. Furthermore, confounding due to unmeasured risk factors such as tobacco smoking could also have impacted our findings, as tobacco smoking is associated with poor clearance of HPV infection [30]. Tobacco smoking sometimes correlates with other lifestyle factors such as increased alcohol consumption, and both of these also increase the risk of several gastrointestinal cancers [31– 34], which may explain, at least in part, the observed increased risk of esophageal, gallbladder and biliary tract, pancreatic, and liver cancers. In addition, esophageal squamous carcinoma is said to be more closely related to smoking compared with adenocarcinoma [35]. As the risk increase for esophageal squamous cell carcinoma was more pronounced than that for esophageal adenocarcinoma, tobacco smoking may have also contributed to the increased risk of esophageal cancer among women with persistent HPV infection. Although smoking may have confounded our findings with regard to cancers strongly related to smoking, such as esophageal squamous cell carcinoma, we observed no association between conization and gastric and colon cancers, which are possibly also related to smoking [36, 37]. Therefore, tobacco smoking is unlikely to entirely explain our findings. We stratified our analyses by the duration of follow-up to examine the temporality of the association between persistent HPV infection and gastrointestinal cancers. This analysis revealed a decrease in overall relative cancer risk with increasing length of follow-up, but the SIRs remained elevated after more than 5 years of follow-up for esophageal, anal, liver, gallbladder and biliary tract, and pancreatic cancers. This finding could indicate an actual association between persistent HPV infection and these cancers, but it could also be attributable to residual confounding from, for example, poor health awareness and lifestyle factors, for which we had no information. Although we also found strongly elevated risks of anal, gallbladder and biliary tract cancers, and colon cancer in
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the first year of follow-up, our estimates had low precision. The increased 1-year risk may result from increased medical surveillance among women undergoing conization for cervical dysplasia (i.e., surveillance bias). In addition, cancers occurring less than 1 year after conization are unlikely to be caused by persistent HPV infection. A major strength of this study is the population-based design in the setting of a uniform tax-financed health care system with equal access for all residents allowing long-term and complete follow-up. The prospective data collection via use of valid electronic registries minimizes the possibilities of underreporting of cancer diagnoses. The increased risk of anal cancer observed in our study is consistent with findings from previous studies, which report a positive association between persistent HPV infection and anal cancer [12], strengthening the validity of our findings. Limitations include a lack of data on potential confounders such as environmental or lifestyle exposures including, among others, tobacco smoking, genetic susceptibility, sexual behavior, and alcohol consumption. We also lacked information on conizations performed at outpatient departments before 1995. Incomplete registration of conization before 1995 would most likely lead to non-differential misclassification and thus an underestimation of a true association. On the other hand, when comparing patients undergoing conization after 1995, we found a lower overall cancer risk among women treated in an outpatient department (data not shown). If such a difference was also present before 1995, we have overestimated the association early in the follow-up period (i.e., before 1995). Moreover, procedures performed at private clinics are not registered in the DNPR and are therefore not included in this study. The proportion of patients treated at private clinics is unknown but probably small due to the tax-financed health care system in Denmark. HPV-infected patients treated by methods other than cervical conization are not included in this study. However, cervical conization is the standard therapy for persistent cervical HPV infection in Denmark, and we, therefore, expect our cohort to comprise the majority of all women treated for persistent HPV infection in the study period. If women with persistent HPV infection are not included in this study, our findings may have been underestimated. In theory, we might have included patients with manifest cervical cancer, which are known to have a higher risk of HPV- and radiation-related secondary cancers [38]. This possible selection problem could lead to an overestimation of gastrointestinal cancer risk. However, only women with very early stages of cervical cancer are treated with conization, and these patients do not require adjuvant radiation therapy. Thus, the observed increase in gastrointestinal cancer risk is unlikely to be explained by a previous history of cervical cancer.
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Whereas chronic HPV infection is known to play a key role in the development of cancers of the anus, uterine cervix, and head and neck [39], the evidence of a role of HPV in the development of esophageal squamous cell carcinoma is inconclusive [13]. This study is the first large registry-based study to investigate the association between chronic HPV infection and other gastrointestinal cancers, which usually have poor survival rates. Our findings imply an increased risk of some gastrointestinal cancers among women with a history of HPV infection, as estimated via cervical conization. Although the absolute risks were low, primary HPV prevention via vaccination may have extended benefit to the control of other cancers. In this hypothesis-generating study, we demonstrated an increased incidence of anal and esophageal cancers, and possible increases in the incidence of gallbladder and biliary tract, pancreatic, and liver cancers more than 5 years after conization. Our findings imply an association between chronic cervical HPV infection and subsequent carcinogenesis in other organs. Acknowledgments The study was supported by a grant from the Danish Cancer Society (R73-A4284-13-S17) and from Aarhus University Research Foundation.
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12.
13.
14.
15.
16. Conflict of interest of interests.
The authors declare that they have no conflict 17.
18.
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